Chandonium

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Chandonium

Candocuronium iodide (formerly recognized as chandonium or HS-310[1]) is the prototypical azasteroidal neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs. Its potential adjunctive use in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation was briefly evaluated in clinical studies in India, but further development was discontinued because of attendant undesirable cardiovasular effects, primarily tachycardia that was no worse than but also not an improvement over the clinically established pancuronium.[2][3][4][5] Chandonium demonstrated a short duration and a rapid onset of action, with little or no ganglion blocking activity, and it was only slightly less potent than pancuronium bromide.[1]

As noted with other well established neuromuscular blocking agents, chandonium preferentially antagonizes competitively the nicotinic subtype of acetycholine receptors.[6] The agent was developed by researchers in the laboratories of Harkishan Singh at the Panjab University in Chandigarh, India, as part of the ongoing search for the Holy Grail of neuromuscular blocking agents: a non-depolarizing replacement for the most popular clinically used depolarizing agent, succinylcholine (suxamethonium).

The mono- and bis-quaternary azasteroid series of compounds (to which chandonium belongs) stems from the same principle that led to the invention of aminosteroids such as pancuronium, vecuronium and rocuronium: the use of the steroid skeleton to provide a somewhat rigid distance between the two quaternary ammoniumm centers with appendages incorporating fragments of choline or acetylcholine. The discovery program, initiated by Singh,[7] initially led to the synthesis of a bis-quaternary non-depolarizing agent labelled HS-342 (4,17a-dimethyl-4,17a-diaza-D-homo-5α-androstane dimethiodide) that was equipotent with tubocurarine and with one-third its duration of action but not suitable for further clinical evaluation.[8][9]

Modifications around the structure of HS-342 led to two other notable agents, HS-347 and HS-310 (subsequently named chandonium).[1][7] HS-347 was equipotent with tubocurarine but also exhibited considerable ganglion blocking activity, whereas chandonium appeared to be suitably placed for clinical trials following encouraging preclinical evaluations.[10][11][12][13]

As already noted, chandonium still did not provide the desirable profile and a further extension of research was undertaken to overcome the limitations of chandonium. This led to four more promising compounds, HS-692, HS-693, HS-704 and HS-705.[14] The onset and duration of these four agents were indinguishable from those of chandonium, but, unfortunately, all demonstrated profound vagolytic effects and much weaker potencies than those of chandonium.[11] To improve on the potency, further modifications of the chandonium nucleus were undertaken, leading to the identification of yet another promising compound, HS-626.[15] Unfortunately, upon further preclinical evaluations in the cat and isolated preparations,[16] it was clearly evident that, although HS-626 demonstrated a slightly more desirable neuromuscular blocking profile than that of chandonium, the overall degree of improvement was insufficient to warrant advancement to clinical testing.

Overall, Singh's research group discovered and identified chandonium which spawned numerous related neuromuscular blocking agents with short durations of action but also attendant with undesirable cardiovascular effects. Subsequent further attempts to attain the intended goal led the group to explore other modifications at the 3 and 16 positions of the androstane nucleus,[17][18] but the admirable undaunted persistence has not yet yielded an agent worthy of expanded evaluation to clinical testing in this azasteroidal class of neuromuscular blocking agents.

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